U.S. Pat. No. 3,075,967, issued Jan. 29, 1963 to John Krapcho describes benzothiazepine derivatives having the formula ##STR2## and salts thereof, wherein X is hydrogen, lower alkyl, lower alkoxy, nitro, halo or trifluoromethyl; each R is hydrogen, lower alkyl, an X-substituted phenyl lower alkyl, an X-substituted phenyl, furyl, thienyl, pyridyl or piperonyl; A is lower alkylene (preferably ethylene and propylene); and B is a basic nitrogen-containing radical of less than twelve carbon atoms. Among the suitable radicals represented by the symbol B are: amino; (lower alkyl)amino; di(lower alkyl)amino; (hydroxylower alkyl)amino; di(hydroxy-lower alkyl)amino; phenyl(lower alkyl)amino; N-(lower alkyl)phenyl (lower alkyl)amino; and saturated 5 to 6 membered monocyclic heterocyclic radicals of less than twelve carbon atoms. The compounds are described as useful for the treatment of Parkinsonism and as tranquilizers.
In J. Med. Chem., 6:544 (1963) and J. Med. Chem., 9:191 (1966), Krapcho et al. discuss compounds falling within the scope of the above patent.
In Chem. Pharm. Bull., 31(5):1780 (1963), Ohno et al. describe cis benzothiazepine derivatives having the formula ##STR3## wherein R is hydrogen, 4-methyl, 4-chloro, 4-methoxy, 3-methyl and 3-chloro, as having anti-ulcer and gastric secretory inhibiting activities.
In Pharmazie, 35:680 (1980) and Pharmazie, 827 (1983), Levai et al. describe benzothiazepines having the formula ##STR4## wherein R.sub.a is hydrogen, 2- or 4-methoxy, 4-isopropyl, 2- or 3-nitro, 2- or 4-chloro, 2,4-, 3,4-or 2,6-dichloro, 2,5-dimethoxy, or 3-hydroxy-4-methoxy, and R.sub.b is hydrogen, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, or 2-(ethoxycarbonyl)ethyl, and trans benzothiazpines having the formula ##STR5## wherein R.sub.c is hydrogen or --(CH.sub.2).sub.n --COOH and n is 0, 1 or 2, R.sub.d is phenyl, specified substituted phenyl groups, 1- or 2-naphthyl, 3-chromonyl, 2-furyl, or 2-thienyl, and R.sub.e is hydrogen, methyl, acetylamino, or phenyl.
Diltiazem, a commercial calcium channel blocking agent, is a cis benzothiazepine having in the 3-position an acetyloxy group. The structural formula of diltiazem is ##STR6## Diltiazem is representative of a large group of cis benzothiazepines having in the 3-position a substituent linked to the benzothiazepine nucleus via an oxygen atom.